I. Field of the Invention
The present invention relates to the fields of medicine, pharmacology and infectious disease. More particular, the invention relates to methods and compositions for treating malarial infections.
II. Related Art
Malaria is a devastating mosquito-borne infectious disease caused by a parasite of the genus Plasmodium, placing over one billion people at high risk for infection. According to the World Health Organization, there were 225 million cases of malaria in 2009 with 781,000 deaths. Although there are a number of drugs used to treat the disease, resistance to most of these drugs is widespread. As a consequence, there is an urgent push for developing antimalarial therapies targeting novel modes of action. Despite this urgent need, most antimalarial drugs in late stage clinical development do not target new mechanisms of action. Rather, these efforts have been focused on enhancing existing antimalarials such as artemisinin. Recently, scientists at GlaxoSmithKline and elsewhere have published on the antimalarial activity of thousands of compounds (Calderon et al., 2011).
Plasmodium has multiple aspartic proteases, including Plasmepsin V (PM-V), which has been demonstrated to be essential to the parasite's survival due to its role in the export of hundreds of Plasmodium proteins to the host erythrocyte. Most early drug discovery efforts in this area have focused on inhibition of the plasmepsins of the digestive vacuole (PM-I, II, IV and III or HAP), but these efforts have not been very successful due to the redundancy of their function. The function of the other plasmepsins (PM-VI, VII, VIII, IX, X) is unknown. It is likely that inhibition of one or more of the plasmepsins, particularly PMs V-X, would be lethal to the parasite. However, there are currently few tools available to identify inhibitors of PMs V-X and no high throughput assays. The only known inhibitors of PM-V are pepstatin A and HIV protease inhibitors such as lopinavir and ritonavir. These inhibitors are weak inhibitors of PM-V (IC50>20 μM) and, due to their large molecular weights and peptidomimetic character, make poor starting points for drug discovery.